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首页> 外文期刊>Oncogene >Regulation of high molecular weight-melanoma associated antigen (HMW-MAA) gene expression by promoter DNA methylation in human melanoma cells
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Regulation of high molecular weight-melanoma associated antigen (HMW-MAA) gene expression by promoter DNA methylation in human melanoma cells

机译：人类黑素瘤细胞中启动子DNA甲基化对高分子量黑素瘤相关抗原（HMW-MAA）基因表达的调控

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The human high molecular weight-melanoma associated antigen (HMW-MAA) is a membrane-bound chondroitin sulfate proteoglycan that is variably expressed in a high percentage of melanoma cell lines and tumors. Since the mechanism(s) regulating HMW-MAA expression has(ve) not been defined, in this study, we have examined whether promoter DNA methylation regulates the level of HMW-MAA expression. In melanoma cell lines, the level of HMW-MAA mRNA and protein expression is coordinately regulated, implicating a transcriptional control mechanism. Consistent with a role for regulation by DNA methylation, we have found that a dense CpG island flanks the human HMW-MAA gene transcriptional start site. Methylation-specific PCR and sodium bisulfite DNA sequencing analyses indicate that the HMW-MAA promoter is heavily methylated in melanoma cell lines, melanoma lesions and normal lymphocytes that do not express HMW-MAA; in contrast, the HMW-MAA promoter is not methylated in melanoma cell lines and tumors that express this antigen. In addition, HMW-MAA expression is markedly induced in HMW-MAA-negative melanoma cell lines by incubation with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine. In summary, our results establish DNA methylation as a key regulator of HMW-MAA expression by human melanoma cells. This information represents a useful background to optimize immunotherapeutic strategies targeting HMW-MAA.
机译：人高分子量黑素瘤相关抗原（HMW-MAA）是膜结合的硫酸软骨素蛋白聚糖，在高百分比的黑素瘤细胞系和肿瘤中可变表达。由于尚未定义调节HMW-MAA表达的机制，因此在本研究中，我们研究了启动子DNA甲基化是否调节HMW-MAA表达的水平。在黑素瘤细胞系中，HMW-MAA mRNA和蛋白质表达的水平受到协调调节，这牵涉转录控制机制。与DNA甲基化调控的作用相一致，我们发现一个密集的CpG岛位于人HMW-MAA基因转录起始位点的侧面。甲基化特异性PCR和亚硫酸氢钠DNA测序分析表明，在不表达HMW-MAA的黑素瘤细胞系，黑素瘤病变和正常淋巴细胞中，HMW-MAA启动子被高度甲基化。相反，HMW-MAA启动子在表达该抗原的黑素瘤细胞系和肿瘤中未甲基化。另外，通过与DNA甲基转移酶抑制剂5-氮杂-2'-脱氧胞苷孵育，在HMW-MAA阴性黑色素瘤细胞系中显着诱导了HMW-MAA表达。总而言之，我们的结果确定了DNA甲基化是人类黑素瘤细胞HMW-MAA表达的关键调节因子。该信息代表了优化针对HMW-MAA的免疫治疗策略的有用背景。

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